In this application, we propose to extend our investigations of the role of inheritance in epilepsy by performing genetic linkage analysis to identify and chromosomally locate specific genes that have a major influence on susceptibility to epilepsy. Approximately 32 families ascertained in the initially funded stage of the project, and known to contain at least three individuals with epilepsy (the proband and at least two first-degree relatives), will be included in the linkage study. Computer simulations will be used to assess (1) which pedigrees are likely to produce the highest lod score, (2) which individuals need to be interviewed to obtain additional family history information, and (3) which individuals need to be sampled within each pedigree. Based on the results of these simulations, additional interviews will be conducted and blood samples collected from informative family members. The genotypes of sampled individuals will be determined at each of a series of genetic markers detected as restriction fragment length polymorphisms. Then the odds of linkage and the maximum likelihood recombination fraction between each genetic marker and a putative susceptibility gene for epilepsy will be estimated. Heterogeneity between families in the recombination fraction will be tested both without assumptions about which families are likely to show linkage, and by comparing families defined by different ages at onset, etiologies, and seizure types in the probands. The phenotype that results from the susceptibility gene will be investigated by comparing the results under several different definitions of affected relatives, including all epilepsy, idiopathic epilepsy only, generalized epilepsies only, partial epilepsies only, both epilepsy and febrile convulsions, and both epilepsy and isolated unprovoked seizures. Finally, if linkage is demonstrated, the presence of linkage disequilibrium will be investigated by comparing marker allele frequencies in affected and unaffected individuals in the study population as a whole. Identification of a susceptibility gene for epilepsy would facilitate early identification of susceptible individuals, and would be a first step in molecular studies designed to identify the physiological mechanism by which susceptibility is raised. Such studies could lead to increased understanding of fundamental factors in the pathogenesis of epilepsy, with corresponding implications for new strategies of treatment and prevention.